bioRxiv Subject Collection: Neuroscience's Journal

An alternative explanation for reported integration and competition between space and time in the hippocampus
Hippocampal place and time cells are thought to be part of the brain's spatial and temporal representation. In the article 'Integration and competition between space and time in the hippocampus', Chen et al. showed that hippocampal neurons with mixed selectivity for space and time shift their firing fields depending on the animal's speed. Here, we reproduce this phenomenon with a simple continuous line attractor that only integrates the animal's velocity. Since our model has no genuine time-encoding capabilities, it constitutes an alternative explanation for Chen et al. findings and challenges the claim that the observed firing field shifts are sufficient evidence for a competitive and integrated representation of space-time, as the authors suggested.

Bidirectional crusher gradient method for estimating the labeling efficiency of pseudo-continuous arterial spin labeling MRI in mice
Pseudo-continuous arterial spin labeling (pCASL) MRI is a widely used imaging technique for studying brain perfusion in health and disease due to its non-invasive and non-contrast nature. Accurate quantification of absolute perfusion values from pCASL signals requires the knowledge of labeling efficiency. However, to date, a reliable technique to measure pCASL labeling efficiency has not been available. In this study, we propose a method using bidirectional crusher gradients to modulate vascular signals in the azygos pericallosal artery (azPA) of the mouse brain, applied with and without pCASL labeling. The combination of corresponding signals allows the estimation of labeling efficiency. Upon systematic testing, optimal acquisition parameters included a labeling duration [≥] 1170 ms, a repetition time of 3 seconds, and an imaging slice thickness of 0.75 mm. In order to quantitatively estimate labeling efficiency, the bolus arrival time to azPA is required and found to be 218.7 +/- 13.3 ms. Typical labeling efficiencies in mouse pCASL scans were 0.780 +/- 0.048 (mean +/- standard deviation). Furthermore, faster arterial flow induced by hypercapnia was found to increase pCASL labeling efficiency. Our method can improve the accuracy of pCASL quantification in mice, offering great potential for advancing its applications in pathophysiological studies.

Neural Mechanisms Linking Global Maps to First-Person Perspectives
Humans and many animals possess the remarkable ability to navigate environments by seamlessly switching between first-person perspectives (FPP) and global map perspectives (GMP). However, the neural mechanisms that underlie this transformation remain poorly understood. In this study, we developed a variational autoencoder (VAE) model, enhanced with recurrent neural networks (RNNs), to investigate the computational principles behind perspective transformations. Our results reveal that temporal sequence modeling is crucial for maintaining spatial continuity and improving transformation accuracy when switching between FPPs and GMPs. The models latent variables capture many representational forms seen in the distributed cognitive maps of the mammalian brain, such as head direction cells, place cells, corner cells, and border cells, but notably not grid cells, suggesting that perspective transformation engages multiple brain regions beyond the hippocampus and entorhinal cortex. Furthermore, our findings demonstrate that landmark encoding, particularly proximal environmental cues such as boundaries and objects, play a critical role in enabling successful perspective shifts, whereas distal cues are less influential. These insights on perspective linking provide a new computational framework for understanding spatial cognition and offer valuable directions for future animal and human studies, highlighting the significance of temporal sequences, distributed representations, and proximal cues in navigating complex environments.

Significance StatementUnderstanding how the brain transforms between different spatial perspectives is crucial for advancing our knowledge of spatial cognition and navigation. This study presents a novel computational approach that bridges the gap between neural recordings and behavior, offering insights into the underlying mechanisms of perspective transformation. Our findings suggest how the brain integrates temporal sequences, distributed representations, and environmental cues to maintain a coherent sense of space. By demonstrating the importance of proximal cues and temporal context, our computational model provides testable predictions for future neurophysiological studies in humans and animals.

Spike inference from calcium imaging data acquired with GCaMP8 indicators
Neuroscience can only be reproducible when its key methods are quantitative and interpretable. Calcium imaging is such a key method which, however, records neuronal activity only indirectly and is therefore difficult to interpret. These difficulties arise primarily from the kinetics, nonlinearity, and sensitivity of the calcium indicator, but also depend on the methods for calcium signal analysis. Here, we evaluate the ability of the recently developed calcium indicator GCaMP8 to reveal neuronal spiking, and we investigate how existing spike inference methods (CASCADE, OASIS, MLSpike) should be adapted for optimal performance. We demonstrate, both for principal cells and interneurons, that algorithms require fine-tuning to obtain optimal results with GCaMP8 data. Specifically, supervised algorithms adapted for GCaMP8 result in more linear and therefore more accurate recovery of complex spiking events. In addition, our analysis of cortical ground truth recordings shows that GCaMP8s and GCaMP8m - but not GCaMP6, GCaMP7f or GCaMP8f - are able to reliably detect isolated action potentials for realistic noise levels. Finally, we demonstrate that, due to their fast rise times, GCaMP8 indicators support shorter closed-loop latencies for real-time detection of neuronal activity. Together, our study provides demonstrations, tools, and guidelines to optimally process and quantitatively interpret calcium signals obtained with GCaMP8.

Neuroscientific Insights into the Built Environment: A Systematic Review of Empirical Research on Indoor Environmental Quality, Physiological Dynamics, and Psychological Well-Being in Real-Life Contexts
The research aims to systematize the current scientific evidence on methodologies used to investigate the impact of indoor built environment on well-being, focusing on Indoor Environmental Quality (IEQ) variables such as thermal comfort, air quality, noise, and lighting. This systematic review adheres to the Joanna Briggs Institute framework and PRISMA guidelines to assess empirical studies that incorporate physiological measurements like heart rate, skin temperature, and brain activity, captured through various techniques in real-life contexts.

The principal results reveal a significant relationship between the built environment and physiological as well as psychological states. For instance, thermal comfort was found to be the most commonly studied IEQ variable, affecting heart activity and skin temperature. The research also identifies the need for a shift towards using advanced technologies like Mobile Brain/Body Imaging (MoBI) for capturing real-time physiological data in natural settings.

Major conclusions include the need for a multi-level, evidence-based approach that considers the dynamic interaction between the brain, body, and environment. The study advocates for the incorporation of multiple physiological signals to gain a comprehensive understanding of well-being in relation to the built environment. It also highlights gaps in current research, such as the absence of noise as a studied variable of IEQ and the need for standardized well-being assessment tools. By synthesizing these insights, the research aims to pave the way for future studies that can inform better design and policy decisions for indoor environments.

Revisiting face-to-hand area remapping in the human primary somatosensory cortex after a cervical spinal cord injury
Spinal cord injury (SCI) leads to profound disruptions in sensorimotor processing. Seminal research in non-human primates suggests that this deprivation of sensory input causes functional remapping within the primary somatosensory cortex (S1). Crucially, cortical somatotopic representations of deprived body parts, such as the hand in cervical SCI, become responsive to touch on intact body parts, such as the face. However, in humans, the evidence for cortical remapping following SCI remains inconclusive. Here, sixteen chronic cervical SCI patients (mean age {+/-} s.e.m. = 52.4 {+/-} 3.5 years; 1 female) and 21 able-bodied controls (age: 49.9 {+/-} 3.4; 2 females) participated in two experiments in which we used a systematic and sensitive approach to determine the full extent of face-to-hand area remapping. In Experiment 1, we employed a lip movement fMRI paradigm, as previously used in human remapping studies. In Experiment 2, we investigated the full architecture of S1 face reorganisation through vibrotactile stimulation of the forehead, lips and chin. Firstly, we assessed whether the level of face activity in the anatomical S1 hand area was increased in SCI patients compared to controls. Secondly, we evaluated potential cortical shifts in peak face activity using geodesic distances. Thirdly, we used representational similarity analysis, where, in the instance of S1 face-to-hand remapping, we anticipated larger representational distances (i.e., more somatotopic information) between the different face sites in the S1 hand area. Finally, we explored what clinical characteristics may be driving face-to-hand area remapping. Our results revealed no significant differences between control participants and tetraplegic patients in any of our three markers for reorganisation during lip movement (Experiment 1) or vibrotactile stimulation (Experiment 2). Furthermore, we found no significant correlations between remapping and the clinical traits of the SCI patients. These findings suggest that cortical reorganisation is not apparent in human cervical SCI patients. As such, the extent of face-to-hand area reorganisation after a human SCI appears to differ fundamentally from what has been observed in experimental models of SCI. Beyond providing essential insights into the limitations of cortical reorganisation in humans, these findings call for a reassessment of rehabilitation strategies based on the assumption of face-to-hand reorganisation after an SCI.

Deciphering Ibogaines Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses
Ibogaine is the main psychoactive alkaloid produced by the iboga tree (Tabernanthe iboga) that has a unique therapeutic potential across multiple indications, including opioid dependence, substance use disorders, depression, anxiety, posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI). We systematically examined the effects of ibogaine, its main metabolite noribogaine, and a series of iboga analogs at monoamine neurotransmitter transporters, some which have been linked to the oneiric and therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with sub-micromolar potency in cell-based fluorimetry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. The iboga compounds also inhibit the plasma membrane monoamine transporters (MATs), prominently including the serotonin transporter (SERT), and a novel iboga target, the organic cation transporter 2 (OCT2). SERT transport inhibition was demonstrated in serotonin axons and soma in the brain and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine showed dual inhibition of VMAT2 and SERT with comparable potency, providing an explanatory model for the known neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the complexity of the iboga pharmacology, which we termed "matrix pharmacology". The matrix pharmacology concept is outlined and used to explain why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors.

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Brain neuromarkers predict self- and other-related mentalizing across adult, clinical, and developmental samples
Human social interactions rely on the ability to reflect on one's own and others' internal states and traits, a psychological process known as mentalizing. Impaired or altered self- and other-related mentalizing is a hallmark of multiple psychiatric and neurodevelopmental conditions. Yet, replicable and easily testable brain markers of mentalizing have so far been lacking. Here, we apply an interpretable machine learning approach to multiple datasets (total N=281) to train and validate fMRI brain signatures that predict 1) mentalizing about the self, 2) mentalizing about another person, and 3) both types of mentalizing. We test their generalizability across healthy adults, adolescents, and adults diagnosed with schizophrenia and bipolar disorder. The classifier trained across both types of mentalizing showed 98% predictive accuracy in independent validation datasets. Self-mentalizing and other-mentalizing classifiers had positive weights in anterior/medial and posterior/lateral brain areas respectively, with accuracy rates of 82% and 77% for out-of-sample prediction. Classifier patterns across cohorts revealed better self/other separation in 1) healthy adults compared to individuals with schizophrenia and 2) with increasing age in adolescence. Together, our findings reveal consistent and separable neural patterns subserving mentalizing about self and others, present at least from the age of adolescence and functionally altered in severe neuropsychiatric disorders. These mentalizing signatures hold promise as mechanistic neuromarkers to measure social-cognitive processes in different contexts and clinical conditions.

Sparse innervation and local heterogeneity in the vibrissal corticostriatal projection
The density and overlap of cortical axons in the dorsolateral striatum (DLS) have suggested that striatal neurons integrate widespread information from cortical regions that are functionally related. However, in vivo, DLS neuronal responses to sensory stimuli have shown unexpectedly high selectivity, raising questions about the actual degree of input convergence of functional corticostriatal projection on individual striatal cells. Here, we investigated this question by focusing on the projections from different whisker cortical columns, as they overlap in the striatum and are co-active during behavior. Using ex vivo patch-clamp recordings in the DLS and glutamate uncaging for focal stimulations in the barrel cortex, we were able to map the location of presynaptic neurons to individual striatal projection neurons (SPNs). We found that each SPN was innervated by cells located in a small number of whisker cortical columns scattered across the barrel field in the slice. Connectivity of single SPNs with cortical neurons was thus highly discontinuous horizontally, despite the presence of more potential connections. Moreover, connectivity patterns were specific to each cell, with neighboring SPNs sharing few common clusters of presynaptic cells in the cortex. Despite this sparse and distinct innervation of individual SPNs, the projection was topographically organized at the population level. Finally, we found similar innervation patterns for D1 and D2-type SPNs, but observed distinct differences in synaptic strength at connections with specific cortical layers, notably with the associative layer 2/3. Our results suggest that the high convergence of somatosensory inputs to the striatum, enabled by diffuse and overlapping cortical innervation, is accomplished through sparse yet complementary connectivity to individual SPNs.

Lifespan Trajectories of the Brains Functional Complexity Characterized by Multiscale Sample Entropy
Resting state functional magnetic resonance imaging (rs-fMRI) is a widely used imaging modality that can capture spontaneous neural activity of the brain. The human brain is a complex system, and emerging evidence suggests that the complexity of neural activity may serve as an index of the brains capacity of information processing. In this study we used multiscale sample entropy (MSE) to analyze the complexity of rs-fMRI timeseries of 504 healthy subjects between the age of 6 to 85 years. We constructed the global and regional trajectories of brains functional complexity over the lifespan and analyzed its correlation with executive function. We observed a nonlinear trajectory of fMRI-complexity over the lifespan with a peak age occurring at 23 (95% CI 21.27, 26.38 years) years of age. Males reach the peak age of complexity at 26 years (95% CI 19.95, 33.14 years) whereas females at 23 (95% CI 20.16, 29.18 years). We found significant correlations between complexity and Number-Letter Switching of Trail Making Test in parietal and medial temporal lobes while Inhibition and Inhibition/Switching of Color Word Interference Test also revealed a significant negative correlation with rs-fMRI complexity in lateral and medial frontal cortex. These results help to understand behavior of fMRI-complexity with aging and reveals association with executive function of the brain. As a non-invasive biomarker, fMRI-complexity could provide novel approach to understand information processing capacity in the brain and deficits thereof in illness.

Local modulation of sleep slow waves depends on timing between auditory stimuli
Conflicting evidence exists regarding the role of the targeted slow-wave phase in determining the direction and spatial specificity of slow-wave activity (SWA) modulation via phase-targeted auditory stimulation (PTAS) during sleep. To reconcile these discrepancies, we re-analyzed high-density electroencephalography (hd-EEG) data from previous studies, focusing on SWA responses to auditory stimuli presented with varying inter-stimulus intervals (ISIs). Our analysis reveals that ISI is a primary determinant of PTAS-induced SWA modulation, exceeding the influence of targeted phase alone. Specifically, auditory stimulation with longer ISIs evoked a global increase in SWA, consistent with a stereotypical auditory-evoked K-complex (KC), independent of targeted phase. Conversely, longer stimulus trains with rapid successive stimulus presentation resulted in spatially localized, phase-dependent SWA modulation, with up-PTAS enhancing and down-PTAS reducing SWA locally around the targeted area. This distinction resolves inconsistencies in prior PTAS studies by demonstrating that phase alone in insufficient in predicting slow-wave responses. Rather, it was the ISI which determined whether PTAS resulted in a global, KC-mediated response or a local, phase-specific modulation of SWA. Consequently, our findings refine the mechanistic understanding of PTAS, suggesting that ISI regulates the engagement of distinct neural circuits and thereby potentially enables the targeted manipulation of specific slow-wave subtypes and their associated functions.

Noradrenergic efferent subsystems that gate traumatic social learning
Individuals experience varying magnitudes of stress in their daily lives. Although stress responses facilitate adaptive processes to cope with changing environments, severe stress can lead to traumatic learning and anxiety disorders. However, the neuronal mechanisms underlying the influence of stress severity on these processes remain unclear. Here, we show that traumatic social stress engages anatomically distinct locus coeruleus noradrenergic (LCNA) subpopulations that exhibit dynamic responses scaled to aversive salience. Using whole-brain activity and axonal projection mappings, we identified projectome subtypes of LCNA neurons, which are differentially recruited by single versus consecutive aversive social experiences. While hippocampus-projecting LCNA neurons responded to general social contacts, thalamus-projecting LCNA neurons tracked the aversive salience of social stimuli. Functional manipulations revealed a bidirectional role of thalamus-projecting LCNA neurons in social avoidance learning. These findings reveal the functional architecture of LCNA subsystems that regulate traumatic social learning via dynamic scaling to aversive salience.

Monkey See, Model Knew: Large Language Models Accurately Predict Visual Brain Responses in Humans and Non-Human Primates
Recent progress in multimodal AI and language-aligned visual representation learning has rekindled debates about the role of language in shaping the human visual system. In particular, the emergent ability of language-aligned vision models (e.g. CLIP) - and even pure language models (e.g. BERT) - to predict image-evoked brain activity has led some to suggest that human visual cortex itself may be language-aligned in comparable ways. But what would we make of this claim if the same procedures could model visual activity in a species that does not have language? Here, we conducted controlled comparisons of pure-vision, pure-language, and multimodal vision-language models in their prediction of human (N=4) and rhesus macaque (N=6, 5:IT, 1:V1) ventral visual activity to the same set of 1000 captioned natural images (the NSD1000). The results revealed markedly similar patterns in model predictivity of early and late ventral visual cortex across both species. This suggests that language model predictivity of the human visual system is not necessarily due to the evolution or learning of language per se, but rather to the statistical structure of the visual world that is reflected in natural language.

Adherence to Lifes Essential 8 Enhances Gut Microbiota Diversity and Cognitive Performance
Emerging evidence suggests a complex interplay among cardiovascular health, gut microbiome composition, and cognitive function. Lifes Essential 8 (LE8), developed by the American Heart Association, includes vital metrics of cardiovascular health, such as diet, physical activity, nicotine exposure, sleep health, body mass index (BMI), blood glucose, blood lipids, and blood pressure. In this study, we analyzed data from 781 participants in the Framingham Heart Study (FHS) to explore the relationship between LE8 adherence, gut microbiota, and cognitive performance. Participants with greater adherence to LE8 demonstrated significantly increased gut microbial diversity (-diversity: Chao1, p = 0.0014; Shannon, p = 0.0071) and distinct microbial compositions ({beta}-diversity: PERMANOVA p = 1e-4). Higher adherence to LE8 was related to an increased abundance of genera Barnesiella and Ruminococcus, while a reduced abundance of Clostridium was associated with higher LE8 adherence. Greater gut microbial diversity (-diversity: Chao1, p = 0.0012; Shannon, p = 0.0066), and beneficial genera like Oscillospira correlated with better global cognitive scores (GCS). Taxonomic overlap analyses revealed microbial taxa that simultaneously influence both LE8 adherence and cognitive outcomes. Mediation analyses indicated that specific taxa, including Barnesiella and Lentisphaerae, mediated the link between LE8 adherence and cognitive performance. These taxa may serve as key modulators in the gut-brain axis, connecting cardiovascular and brain health. Conversely, higher Clostridium abundance was associated with poorer cognitive performance. This study highlights the significance of comprehensive cardiovascular health metrics in shaping gut microbiota and enhancing cognitive resilience. Our findings underscore the therapeutic potential of targeting gut microbiota to mitigate cognitive decline, warranting further exploration through longitudinal and metagenomic studies.

Activity in serotonergic axons in visuomotor areas of cortex is modulated by the recent history of visuomotor coupling
Visuomotor experience is necessary for the development of normal function of visual cortex (Attinger et al., 2017) and likely establishes a balance between movement-related predictions and sensory signals (Jordan and Keller, 2020). This process depends at least in part on plasticity in visual cortex (Widmer et al., 2022). Key signals involved in driving this plasticity are visuomotor prediction errors (Keller et al., 2012; Keller and Mrsic-Flogel, 2018). Ideally however, the amount of plasticity induced by an error signal should be a function of several variables - including overall cortical prediction error, the animal's experience in the current environment or task, stability of the current environment, and task engagement - for optimal computational performance. Candidates for regulators of visuomotor prediction error driven plasticity are the three major neuromodulatory systems that innervate visual cortex in the mouse: acetylcholine, noradrenaline, and serotonin. While visuomotor mismatch acutely triggers activity in noradrenaline (Jordan and Keller, 2023) but not acetylcholine (Yogesh and Keller, 2023) axons in visual cortex, how serotonergic axons in cortex respond to visuomotor mismatch is unknown. The serotonergic system in particular, is an interesting candidate for regulating visuomotor plasticity, as its activity is correlated with action-outcome uncertainty in mice (Grossman et al., 2020), and is increased under conditions of higher visuomotor gain in larval zebra fish (Kawashima et al., 2016). Here, we characterized the activity of serotonergic axons in visual cortex (V1) and in area A24b, a motor cortical area in anterior cingulate cortex (ACC), of awake head-fixed mice using two-photon calcium imaging. Our results reveal cortical region-specific responses to visuomotor stimuli in serotonergic axons, but no evidence of a response to visuomotor mismatch. However, average activity in serotonergic axons was increased under conditions of greater visuomotor uncertainty. Thus, serotonin could function to regulate visuomotor plasticity as a function of the predictability of the environment on longer time scales.

EEG-derived Brain Connectivity in Theta/Alpha Frequency Bands Increases During Reading of Individual Words
Objective: Although extensive insights about the neural mechanisms of reading have been gained via magnetic and electrographic imaging, the temporal evolution of the brain network during sight reading remains unclear. We tested whether the temporal dynamics of the brain functional connectivity involved in sight reading can be tracked using high-density scalp EEG recordings. Approach: Twenty-eight healthy subjects were asked to read words in a rapid serial visual presentation task while recording scalp EEG, and phase locking value was used to estimate the functional connectivity between EEG channels in the theta, alpha, beta, and gamma frequency bands. The resultant networks were then tracked through time. Main results. The network's graph density gradually increases as the task unfolds, peaks 150-250-ms after the appearance of each word, and returns to resting-state values, while the shortest path length between non-adjacent functional areas decreases as the density increases, thus indicating that a progressive integration between regions can be de-tected at the scalp level. This pattern was independent of the word's type or position in the sentence, occurred in the theta/alpha band but not in beta/gamma range, and peaked earlier in the alpha band compared to the theta band (alpha: 184 {+/-} 61.48-ms; theta: 237 {+/-} 65.32-ms, P-value P<0.01). Nodes in occipital and frontal regions had the highest eigenvector centrality throughout the word's presentation, and no significant lead-lag relationship between frontal/occipital regions and parietal/temporal regions was found, which indicates a consistent pattern in information flow. In the source space, this pattern was driven by a cluster of nodes linked to sensorimotor processing, memory, and semantic integration, with the most central regions being similar across subjects. Significance. These findings indicate that the brain network connectivity can be tracked via scalp EEG as reading unfolds, and EEG-retrieved networks follow highly repetitive patterns lateralized to frontal/occipital areas during reading.

Hippocampal Ripple Diversity organises Neuronal Reactivation Dynamics in the Offline Brain
Hippocampal ripples are highly synchronized neuronal population patterns reactivating past waking experiences in the offline brain. Whether the level, structure, and content of ripple-nested activity are consistent across consecutive events or are tuned in each event remains unclear. By profiling individual ripples using laminar currents in the mouse hippocampus during sleep/rest, we identified Radsink and LMsink ripples featuring current sinks in stratum radiatum versus stratum lacunosum-moleculare, respectively. These two ripple profiles recruit neurons differently. Radsink ripples integrate recent motifs of waking coactivity, combining superficial and deep CA1 principal cells into denser, higher-dimensional patterns that undergo hour-long stable reactivation. In contrast, LMsink ripples contain core motifs of prior coactivity, engaging deep cells into sparser, lower-dimensional patterns that undergo a reactivation drift, gradually updating their pre-structured content for recent wakefulness. We propose that ripple-by-ripple diversity instantiates parallel reactivation channels for stable integration of recent wakefulness and flexible updating of prior internal representations.

Identification of a neural basis for energy expenditure in the arcuate hypothalamus
Given the evolutionary instinct for caloric intake and the tendency for weight rebound after discontinuing dietary interventions or medications, increasing energy expenditure emerges as an alternative obesity treatment. However, neural regulation of energy expenditure remains poorly understood. Here, we report that a hypothalamic neuronal subtype, characterized by Crabp1 expression, establishes connections with multiple hypothalamic nuclei to regulate energy expenditure in mice. Inactivation of Crabp1 neurons reduces physical activity, body temperature, and adaptive thermogenesis, leading to an obese phenotype. Conversely, activation of these neurons increases energy expenditure and mitigates diet-induced obesity. Structural and functional analyses reveal that Crabp1 neurons promote energy metabolism through a "one-to-many" projection pattern. While Crabp1 neurons are rapidly activated by cold exposure and physical activity, prolonged light exposure abrogates their firing and may mediate light-induced metabolic disorder. Together, we reveal a neural basis that integrate various physiological and environmental stimuli to control energy expenditure and body weight.

Distributed burst activity in the thalamocortical system encodes reward contingencies during learning
Neuronal bursts are distinct high-frequency firing patterns that are present ubiquitously throughout mammalian brain circuits. Although bursts are considered part of a universal neural code, the information they convey has long been a subject of debate. In this study, we investigated neuronal activity in simultaneously recorded regions of the thalamocortical system in freely moving mice as they learned stimulus-outcome associations in a go/no-go task. We discovered that, in parallel with learning, populations of neurons emerge in cortical, thalamic, and extrathalamic regions of the somatosensory system that encode task-relevant stimulus features via the presence or absence of bursts. These burst-coder neurons (BCNs) increase in number with task proficiency and exhibit burstiness that scales with stimulus valence rather than physical stimulus identity. Notably, BCNs consistently track stimulus-outcome associations--even after multiple rule switches--by inverting their burst encoding of the physical stimuli, indicating that burst coding is driven by outcome associations rather than by inherent stimulus properties. Although burst coding emerges throughout the thalamocortical system, only cortical units retain significant burst coding after devaluation, while other regions lose their discriminative burst patterns. Furthermore, decoding of stimulus properties and behavior achieves maximal accuracy when bursts or BCNs are used as input. Overall, these results provide direct experimental evidence linking neuronal bursting to learning, supporting a novel perspective of bursts as context encoders and teaching signals.

Multimodal brain cell atlas across the adult macaque lifespan
High-throughput single-cell omics of non-human primate tissues present a remarkable opportunity to study primate brain aging. Here, we introduce a transcriptomic and chromatin accessibility landscape of 1,985,317 cells from eight brain regions of 13 cynomolgus female monkeys spanning adult lifespan including exceptionally old individuals up to 29-years old. This dataset uncovers dynamic molecular changes in critical brain functions such as synaptic communication and axon myelination, exhibiting a high degree of cell type and brain region specificity. We identify the multicellular networks of the pons and medulla as a previously unrecognized hotspot for aging. Furthermore, comparative analyses with human neurodegeneration datasets highlight both shared and distinct mechanisms contributing to aging and disease. In addition, we uncover transcription factors implicated in monkey brain aging and pinpoint aging-regulated loci linked to longevity and neurodegeneration. This spatiotemporal atlas will advance our understanding of primate brain aging and its broader implications for health and disease.

Alpha and Beta Oscillations Mediate the Effect of Motivation on Neural Coding of Cognitive Flexibility
Cognitive flexibility is crucial for adaptive human behaviour. Prior studies have analysed the effect of reward on cognitive flexibility; however, the neural mechanisms underlying these effects remain largely unknown. This study explores how reward influences neural oscillations and how these changes impact behavioural performance. Using time-frequency decomposition, we examined electroencephalographic data from participants engaged in rule-guided task-switching with varying reward prospects. Higher anticipated rewards lead to greater desynchronisation of alpha (8-12Hz) and beta (20-30Hz) oscillations, which in turn correlated with improved task performance. Both alpha power and event-related potential (ERP) coding of reward independently predicted reward-based performance improvements, suggesting distinct mechanisms supporting proactive control. These findings underscore the unique contributions of neural oscillations in mediating motivational effects on cognitive flexibility.

Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity
Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimers disease (AD). Increases in cytosolic noradrenaline (NA) concentration and MAO-A activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-{beta}-hydroxylase. Since re-uptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of 2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of 2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of 2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP) and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of 2A-ARs/GIRK is accompanied by [Ca2+]i increases, subsequently increasing Ca2+-dependent MAO-A activity and NA-autocrine. Thus, it is likely that internalization of 2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating re-uptake of autocrine-released NA. The suppression of 2A-AR internalization has a strong translational potential for AD.

Visualization of stochastic expression of clustered protocadherin β isoforms in vivo
The stochastic expression of clustered protocadherin (cPcdh) establishes a single-cell identity fundamental to cellular self/non-self-discrimination. However, it has been challenging to reveal the spatiotemporal patterning of the stochastic cPcdh expression in vivo. We developed XFP (tdTomato or GFP) knock-in mice using a new strategy to enhance XFP expression, which allows us to visualize cPcdh{beta}3 or 19-positive cells throughout the brain. These mouse lines demonstrate the cell-type selectivity, spatial biases, inter-individual differences, left-right asymmetry, developmental regulation, alteration in pathological or aging brain, and monoallelic expression of stochastic cPcdh{beta} expression in vivo. Our findings further demonstrate that the cPcdh{beta}3 expression undergoes significant changes in the mature brain over time. These results demonstrate the potential of these reporter mice to advance our understanding of cPcdh cellular barcode in vivo.nnOne Sentence SummaryNovel established cPcdh{beta} reporter mouse lines reveal stochastic expression of cPcdh{beta} isoforms in vivo.

Prenatal DEHP plastic chemical exposure increases the likelihood of child autism and ADHD symptoms through epigenetic programming
Increasing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plastic chemical, in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms are poorly understood. Here we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and ASD/ADHD symptoms in 847 children enrolled in the Barwon Infant Study. ASD and ADHD are complex phenotypes characterised by differences at the gene regulatory network and neuronal circuit level, where heterogeneous genetic and environmental risk factors converge. Accordingly, we employed a data-driven computational strategy that helped elucidate broader functional epigenetic signatures of ASD and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPSDEHP), and (2) an analysis of co-methylated gene networks. Causal mediation analysis demonstrated that both MPSDEHP and a DEHP-associated network of co-methylated genes mediated the effect of DEHP exposure on increased ASD and ADHD symptoms at ages 2 and 4 years (proportion of effect mediated ranged from 0.21 to 0.80). The co-methylation network was enriched for neural cell-type markers, ASD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including targets of the estrogen receptor ER and the glucocorticoid receptor GR), providing biological plausibility. We validated key results in independent blood (n=66) and postmortem brain (n=40) DNA methylation datasets. These findings provide mechanistic evidence linking DEHP to ASD and ADHD symptoms and reinforce growing concerns regarding the risks of prenatal exposure.nnSignificanceExposure to endocrine-disrupting plastic chemicals has been linked to adverse neurodevelopment, but the underlying biological mechanisms remain unclear. We demonstrate that prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, increases autism and ADHD symptoms through alterations in DNA methylation, a key epigenetic regulator of gene activity. Using birth cohort data, we identify epigenetic signatures of prenatal DEHP exposure, including alterations in an endocrine-related co-methylation network enriched for neural cell-type markers and known autism-associated genes. These signatures mediate the effects of DEHP on autism and ADHD symptoms and are also associated with autism in external blood and postmortem-brain datasets, providing independent validation. This causal evidence further underscores concerns regarding the consequences of prenatal plastic-chemical exposure on the developing brain.

Pathological α-Synuclein Perturbs Nuclear Integrity
Pathological aggregates of -synuclein are a hallmark of a group of neurodegenerative disorders collectively termed synucleinopathies. The physiological function of -synuclein and the detrimental effects of the pathological variants of -synuclein have been widely debated, but recent evidence has suggested an emerging consensus on a critical role for -synuclein in regulating synaptic function. However, a controversial role for -synuclein in nuclear function in both normal and pathogenic states has been proposed, and the degree to which -synuclein localizes within the nucleus and subsequent impact on the nucleus are poorly understood. To begin to address this controversy, we employed synucleinopathy murine and cell culture models, as well as postmortem human Lewy Body Dementia tissue to elucidate the extent to which pathological -synuclein localizes within the nuclear compartments, and the downstream consequences of this localization. We observed pathological aggregation of -synuclein within the nucleus in both murine models and human postmortem Lewy Body Dementia cortex via quantitative super resolution microscopy. In both mouse and human brain tissue the presence of -synuclein in the nucleus correlated with abnormal morphology of nuclei. This pathological accumulation of -synuclein in the nucleus was not observed in control mice, human tissue without pathology, or control cells. We subsequently examined the mechanistic consequences of pathological accumulation of -synuclein in the nucleus. Synucleinopathy models displayed increased levels of the DNA damage marker 53BP1. Furthermore, cells with pathological -synuclein exhibited elevated markers of nuclear envelope damage and abnormal expression of nuclear envelope repair markers. Our cell culture data also suggests altered RNA localization in response to pathological -synuclein accumulation within the nucleus. Lastly, we show that nuclear Lewy-like pathology leads to increased sensitivity to nuclear targeted toxins. Taken together, these results rigorously illustrate nuclear localization of pathological -synuclein with super resolution methodology and provide novel insight into the ensuing impact on nuclear integrity and function.

Dual agonist and antagonist muscle vibration produces a bias in end point with no change in variability
Muscle spindles provide critical proprioceptive feedback about muscle length to the central nervous system (CNS). Single muscle tendon vibration can stimulate muscle spindles, causing participants to misjudge limb position, while dual muscle tendon vibration is thought to produce a noisy proprioceptive system. It is currently unclear exactly how the CNS uses kinesthetic feedback from the agonist and antagonist muscles during target-directed reaches. The purpose of the current project was to investigate the effects of agonist, antagonist, and dual agonist/antagonist during target-directed reaching. Using an elbow extension task, we found that antagonist muscle vibration produced an undershooting effect relative to the no-vibration control, while agonist muscle vibration produced an overshooting effect relative to the no-vibration control. Neither of the single muscle vibrations produced any change in the variable error of the movements. While it was originally hypothesized that dual agonist/antagonist vibration would increase participants variable error with no change in bias, the opposite was found. Participants undershot relative to the no-vibration control with no change in variable error. Overall, the results from this study suggest that dual vibration does not necessarily create a noisy proprioceptive system but can produce a bias in end point.